D(_)-and l(+)-threo-1-p-nitrophenyl-2-n,n-dimethylamino-propane 1,3 - diols and the salts thereof



United States Patent Int. (:1. can 91/16 US. Cl. 260570.6 3 ClaimsABSTRACT OF THE DISCLOSURE Optical isomers of1-p-nitrophenyl-2-N,N-dimethylamino-propane-l,3-diol and acid additionsalts thereof, useful for the separation of racemic compounds andpreparation thereof.

Prior art The importance of the separation of racemic compounds such asracemic acids, which are formed in the synthesis of natural products ofwhich only one isomer is active, is well known. The resolution ofracemic acids is currently effected by combining the acid with anoptically active base to form a mixture of two diastereoisorneric saltswhich can be separately recovered and purified and then decomposed intothe corresponding dextrorotatory' or levorotatory acid. Optically activebases such as brucine, morphine, quinine, L(+)-threo-l-p-nitrophenyl-2-amino-propane-1,3-diol, etc., have been used as resolution agents.

However, tests have shown that the resolution of an acid very often runsinto great difiiculties of a technical nature which cannot be predicted.The base should form easily crystallizable stable salts with one of thediastereoisomeric salts being distinctly less soluble than the other inorder to facilitate the separation of the salts. Also, the base to beseparaed should preferably be slightly soluble in aqueous media so thatit may be recovered without great difficulty after decomposition of itssalt.

Objects of the invention It is an object of the invention to providenovel, optically active isomers of1-p-nitrophenyl-2-N,N-dimethylamino-propane-lfialiol and its acidaddition salts.

It is another object of the invention to provide a novel process for thepreparation of the optically active isomers of1-p-nitrophenyl-2-N,N-dimethylamino-propane-1,3-diol and its acidaddition salts.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

The novel compounds of the invention consist of D() threo l pnitrophenyl 2 N,N dimethylamino-propane-l,3-diol andL(+)-threo-l-p-nitrophenyl- 2-N,N-dimethylamino propane 1,3-diol andtheir acid addition salts. The said diastereoisomers are unexpectedlyexcellent agents for the resolution of racemic acids since they formsalts of greater stability and better crystallizability and the basesare less soluble in aqueous media than known remlving agents such asephedrine or L(+)- threo-l-p-nitro henyl-Z-amino-propane-1,3-diol.

The diastereoisomers of the invention are particularly useful for theresolution of racemic mixtures of 1,5-dioxo- 7a-loweralkyl-S,6,7,7a-tetrahydroindane-4-acetic acids which have been difficultto separate with known resolution agents due to the very slightsolubility diiferences and poor stability of diastereoisomeric saltsformed therewith, such as with L(+)-threo-l-p-nitrophenyl-Z-amino-3,499,929 Patented Mar. 10, 1970 propane-1,3-diol. Other racemic acidsalso may be resolved with the novel compounds of the invention andexamples of said acids are polyhydronaphthalenic acids, tetrahydroindaneacids and a-amino acids.

1,5 dioxo 7a methyl 5,6,7,7a tetrahydroindane 4-acetic acid, which isdescribed in French Patent No. 1,384,854, is useful as an intermediatefor the preparation of various steroids, such as B-nor-steroids andestradiol derivatives. To resolve a racemic mixture of the said acid,D(-) threo 1 p nitrophenyl 2 N,N dimethylamino-propane-l,3-diol can beadded to a solution of the racemic acid in an ethylacetate-ethanol-Water solvent to crystallize the dextrorotatory salt ofD()-threo-l-pnitrophenyl 2 N,N dimethylamino propane 1,3 diol withdextrorotatory 1,5-dioxo-7a-methyl-5,6,7,7atetrahydroindane-4-aceticacid, separating the said crystals from the mother liquor, treating thecrystals with first alkaline conditions and then acid conditions torecover 1,5 dioxo 7a methyl 5,6,7,7a tetrahydroindane-4-acetic acidhaving a melting point of 129 C. and a specific rotation of [u] ='+225:l(0.5% in water), evaorating the mother liquor taking up in water theresidue, treating the aqueous solution with alkaline conditions,separating the crystals formed, acidifying the filtrate, then purifyingthe reaction mixture, extracting with an organic solvent, evaporatingthe extracts and treating the residue withL(+)-threo--l-p-nitrophenyl-Z- N,N-dimethylamino-propane-1,3-diol toform the corresponding levorotatory salt which can be subjected toalkaline and then acid treatment to obtain ()-1,5- dioxo 7a methyl5,6,7,7a tetrahydroindane 4 acetic acid with a melting point of 129 C.and a specific rotation of [a] ='-Z25i"1 (0.5% in water). Of course, theorder of addition of the optically active isomers of the invention maybe reversed with the levorotatory salt being recovered first.

The process of the invention for the preparation of the threo 1 pnitrophenyl 2 N,N dimethylamino propane-1,3-diols comprises subjecting adiastereoisomer of threo p nitrophenyl 2 amino propane 1,3 diol toreductive alkylation with a mixture of formaldehyde and formic acid toform the corresponding N,N-dimethylamino compound, which can beconverted into an acid addition salt with an organic or inorganic acid.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE I Preparation of D() and L( )-threo-l-p-nitrophenyl-2-N,N-dirnethylamino-propane-1,3-diols A reaction mixture of 50 gm. ofD()-threo-l-pnitrophenyl-2-amino-propane-1,3-diol, 50 cc. of 30% formoland 50 cc. of 98% formic acid was heated for about 3 hours in a steambath after which it was distilled to dryness under vacuum. The oilyresidue obtained was dissolved in 150 cc. of water and after 40 cc. of a22 B. ammonium hydroxide were added, the mixture was maintained forabout 15 minutes at a temperature of about C. Then, 60 cc. of ammoniumhydroxide were again added at a high temperature and the entire mixturewas allowed to stand at a low temperature for about 1 hour. Thereafter,the crystals formed were vacuum filtered, washed with water and driedunder exclusion of light, to obtain 53.5 gm. ofD()-threo-l-p-nitrophenyl- 2-N,N-dimethylamino-propane-1,3-diol. Theproduct was then purified by dissolution in 2 N hydrochloric acid,followed by treatment with animal black, and recrystallization byaddition of N-sodium hydroxide. Thus by starting with 121.6 gm. of rawproduct, 113 gm. of

pure product having a melting point of 101 C. and a specific rotation of[u] =26il (c.=1% in ethanol), were obtained. The product was slightlysoluble in water and soluble in dilute aqueous acids and alcohols.

Analysis.-Calcd for C H O N (percent), molecular weight:240.25: C,54.99; H, 6.71; N, 11.66. Found (percent): C, 55.2; H, 7.0; N, 11.5.

This compound is not described in the literature.

L(+)-threo-1-p-nitrophenyl 2 N,N-dimethylaminopropane-1,3-diol wasprepared by starting with L(+)- threo-l-p-nitrophenyl 2amino-propane-1,3-diol according to the above method and had a meltingpoint of 101 C. and a specific rotation of [u] :+26il (c.=1% inethanol). The product was slightly soluble in water and soluble indilute aqueous acids and alcohols.

Analysis.-Calcd for C H O N (percent), molecular Weight=240.25: C,54.99; H, 6.71; N, 11.66. Found (percent): C, 55.0; H, 6.7; N, 11.4.

This compound is not described in the literature. The starting compoundswere prepared according to the process described by J. Controulis etal., J.A.C.S. 71, p. 2463 (1949).

EXAMPLE II Resolution of1,5-dioxo-7a-methyl-5,6,7,7a-tetrahydroindane-4-acetic acid Step A.Preparation of the dextrorotatory salt of D( threo-l-p-nitrophenyl 2,N,Ndimethylamino-propane- 1,3-diol with dextrorotatory1,5-dioxo-7a-methyl-5,6,7,7atetrahydroindane-4-acetic acid: 22.2 gm. ofracemic 1,5- dioxo-7a-methyl'5,6,7,7a-tetrahydroindane-4 acetic acid and24 gm. of D()-threo-1-p-nitrophenyl-2-N,N-dimethylamino-propane-l,3-diolwere dissolved at reflux in 100 cc. of ethyl acetate containing 2% ofwater and 7 cc. of ethanol. Crystallization was started and the solutionwas allowed to cool to room temperature over about 2 hours and then itwas allowed to stand at a low temperature for 12 hours. The crystalsformed were vacuum filtered, washed repeatedly with ethyl acetatecontaining 1% of water and finally dried to obtain 21.84 gm. of thedesired salt having a melting point of about 100 C. and a specificrotation of [a] =+78i1 (c.:1% in water). The product was soluble inwater and in alcohol and slightly soluble in ethyl acetate.

This compound is not described in the literature.

Step B. Preparation of dextrorotatory1,5-dioxo-7amethyl-5,6,7,7a-tetrahydroindane-4-acetic acid: 24 gm. ofthe dextrorotatory salt of D()-threo-1-p-nitrophenyl-2-N,N-dimethylamino-pr0pane 1,3 diol with dextrorotatory1,5-dioxo-7a-methyl-5,6,7,7a-tetrahydroindane-4- acetic acid wereintroduced into 100 cc. of ice water under an atmosphere of nitrogen.Then 50 cc. of N-sodium hydroxide were very slowly and under agitationadded to the reaction mixture. The reaction mixture was then filteredand the filtrate was recovered, washed repeatedly with ethyl acetate,then acidified with concentrated hydrochloric acid. Ammonium sulfate Wasadded until saturation was attained, and finally, the reaction mixturewas extracted several times with methylene chloride. The extracts werecombined, dried over magnesium sulfate, treated with animal black andevaporated to dryness under vacuum.

The residue was taken up in 20 cc. of toluene, and allowed to stand forcrystallization. The crystals formed were vacuum filtered, washed withiced toluene and dried to obtain 10.5 gm. of dextrorotatory11,5-diXo-7a-methyl-5,6,7,7a-tetrahydroindane-4-acetic acid having amelting point of 129 C. and a specific rotation of [u] +225 i1" (c.=0.5%in water). The product was slightly soluble in toluene, fairly solublein water and soluble in alcohols and in chloroform.

Step C. Preparation of the levorotatory salt of L(+)-threo-1-p-nitrophenyl-2 N,N dimethylamino-propane-l, 3,-diol withlevorotatory 1,5-dioxo 7a methyl-5,6,7,7atetrahydroindane-4-acetic acid:Using the procedure of Step A, the resolution of 61.5 gm. of racemic1,5-dioxo- 7a-methyl-5,6,7,7a-tetrahydroindane-4-acetic acid waseffected with 68 gm. of D()-threo-1p-nitrophenyl-2-N,N-dimethylarnino-propane-1,3-diol to form the dextrorotatory salt ofD()-threo-l-p-nitrophcnyl-2-N,N-dimethylamino-propane-1,3-diol withdextrorotatory 1,5-dioxo- 7a-methyl-5,7,7,7a-tetrahydroindane-4-aceticacid which precipitated. The mother liquors were recovered andevaporated to dryness under vacuum and the oily residue was taken up inwater. The solution was made alkaline by the addition of aqueous sodiumhydroxide and then was filtered to separate the crystals formed whichwere then washed several times with water. The filtrate and the washwaters were combined, washed with ethyl acetate and then acidified withhydrochloric acid. Ammonium sulfate was added until saturation wasattained and after the residual racemic acid, which then precipitatedwas separated, the saturated solution of ammonium sulfate was repeatedlyextracted with methylene chloride. The extracts were combined, driedover magnesium sulfate, treated with animal black, filtered andevaporated to dryness under vacuum. The residue was dissolved, underreflux, with 30 gm. of L(+)-threo-1-p-nitrophenyl-2-N,N-dimethylamino-propane-1,3-diol in cc. of ethyl acetate containing2% of water. Crystallization was started and the mixture was allowed tostand overnight. Then the crystals formed were vacuum filtered, washedwith ethyl acetate containing 2% of water and dried. After theirpurification, 51.1 gm. of the desired salt having a specific rotation of[a] =78 1 (c.=1% in water), were obtained. The product was slightlysoluble in ethyl acetate and soluble in water and in alcohols.

This compound is not described in the literature.

Step D. Preparation of levorotatory1,5-dioxo-7a-methyl-5,6,7,7a-tetrahydroindane-4-acetic acid: The saltobtained in Step C was decomposed as was the dextrorotatory acid in StepB to obtain levorotatory1,5-dioxo-7amethyl-5,6,7,7a-tetrahydroindane-4-acetic acid having amelting point of 129 C. and a specific rotation of [a] =225i1 (c.=0.5%in water). The product was slightly soluble in toluene, fairly solublein water and soluble in alcohols and in chloroform.

Various modifications of the process and products of the invention maybe made without departing from the spirit or scope thereof.

We claim:

1. A compound selected from the group consisting of D()-threo-1p-nitrophenyl 2 N,N-dimethylaminopropane-1,3-diol and L(-threo-1-p-nitrophenyl-2-N,N- dimethylamino-propane-1,3-diol and theiracid addition salts.

2. A compound of claim 1 which isD()-threo-1-pnitrophenyl-2-N,N-dimethylamino-propane-1,3-diol.

3. A compound of claim 1 which isL(+)-threo-l-pnitrophenyl-2-N,N-dimethylamino-propane-1,3-diol.

References Cited Adams et 211.: Organic Reactions, vol. 5, pages 307,317 and 325 (1949).

Funke et al.: Chemical Abstracts, vol. 48, page 5141 ROBERT V. HINES,Primary Examiner s. c1. X.R 260-514, 501.17

